The NOX family of NADPH oxidases play a vital role in host defense through the generation of microbicidal reactive oxygen species (ROS). The P.I. hypothesizes that polymorphisms in these genes play a major role in susceptibility or resistance to B. anthracis infection. In addition to the catalytic subunits, the activity of these enzymes is tightly regulated by a family of accessory proteins. In view of the potential fundamental importance of these proteins to B. anthracis resistance, this proposal aims to provide a better understanding of their function, expression, and regulation. Elevated ROS may act positively by enhancing killing of B. anthracis by ROS and increasing cytokine production. Alternatively, increased ROS may suppress host defense by accelerating macrophage lysis. The long-term objectives of the proposed research are to provide information that may identify risk factors and therapies to combat biowarfare agents as described in the following Specific Aims: 1) Examination of polymorphisms in phox/NOX genes and their relationship to B. anthracis susceptibility/resistance. The P.I. proposes to use an existing large (>40,000 individuals) DNA repository at TSRI to identify these polymorphisms. Each DNA sample is linked to an extensive health record that will enable associations to be made between phox and NOX polymorphisms and susceptibility to disease (for instance pulmonary infection). 2). Study of the functional activity of the NOX homologs, their regulation and the effects of polymorphisms. These studies will address the hypothesis that the NOX isoforms have polymorphisms affect their activity. 3). Tissue localization of NOX family members. The P.I. proposes to examine barrier tissues for the presence of NOX family proteins and changes in their expression levels in response to B. anthracis challenge. Particular attention will be paid to human lung tissue, as this is the most likely route of exposure to B. anthracis.